Abstract
BackgroundCuS-modified hollow mesoporous organosilica nanoparticles (HMON@CuS) have been preferred as non-invasive treatment for cancer, as near infrared (NIR)-induced photo-thermal effect (PTT) and/or photo-dynamic effect (PDT) could increase cancer cells’ apoptosis. However, the certain role of HMON@CuS-produced-PTT&PDT inducing gastric cancer (GC) cells’ mitochondrial damage, remained unclear. Moreover, theranostic efficiency of HMON@CuS might be well improved by applying multi-modal imaging, which could offer an optimal therapeutic region and time window. Herein, new nanotheranostics agents were reported by Gd doped HMON decorated by CuS nanocrystals (called HMON@CuS/Gd).ResultsHMON@CuS/Gd exhibited appropriate size distribution, good biocompatibility, l-Glutathione (GSH) responsive degradable properties, high photo-thermal conversion efficiency (82.4%) and a simultaneous reactive oxygen species (ROS) generation effect. Meanwhile, HMON@CuS/Gd could efficiently enter GC cells, induce combined mild PTT (43–45 °C) and PDT under mild NIR power density (0.8 W/cm2). Surprisingly, it was found that PTT might not be the only factor of cell apoptosis, as ROS induced by PDT also seemed playing an essential role. The NIR-induced ROS could attack mitochondrial transmembrane potentials (MTPs), then promote mitochondrial reactive oxygen species (mitoROS) production. Meanwhile, mitochondrial damage dramatically changed the expression of anti-apoptotic protein (Bcl-2) and pro-apoptotic protein (Bax). Since that, mitochondrial permeability transition pore (mPTP) was opened, followed by inducing more cytochrome c (Cyto C) releasing from mitochondria into cytosol, and finally activated caspase-9/caspase-3-depended cell apoptosis pathway. Our in vivo data also showed that HMON@CuS/Gd exhibited good fluorescence (FL) imaging (wrapping fluorescent agent), enhanced T1 imaging under magnetic resonance imaging (MRI) and infrared thermal (IRT) imaging capacities. Guided by FL/MRI/IRT trimodal imaging, HMON@CuS/Gd could selectively cause mild photo-therapy at cancer region, efficiently inhibit the growth of GC cells without evident systemic toxicity in vivo.ConclusionHMON@CuS/Gd could serve as a promising multifunctional nanotheranostic platform and as a cancer photo-therapy agent through inducing mitochondrial dysfunction on GC.
Highlights
CuS-modified hollow mesoporous organosilica nanoparticles (HMON@CuS) have been preferred as non-invasive treatment for cancer, as near infrared (NIR)-induced photo-thermal effect (PTT) and/or photo-dynamic effect (PDT) could increase cancer cells’ apoptosis
Hollow mesoporous organosilica nanoparticles (HMON)@CuS/Gd could serve as a promising multifunctional nanotheranostic platform and as a cancer photo-therapy agent through inducing mitochondrial dysfunction on gastric cancer (GC)
Mesoporous organosilica nanospheres with large pore were firstly synthesized by the dual hydrolysis and condensation of bis[3-(triethoxysilyl) propyl]tetrasulfide (BTES) and TEOS under the catalyzation of TEA, while Cetyltrimethylammonium chloride solution (CTAC) was used for pore forming
Summary
CuS-modified hollow mesoporous organosilica nanoparticles (HMON@CuS) have been preferred as non-invasive treatment for cancer, as near infrared (NIR)-induced photo-thermal effect (PTT) and/or photo-dynamic effect (PDT) could increase cancer cells’ apoptosis. The certain role of HMON@CuS-produced-PTT&PDT inducing gastric cancer (GC) cells’ mitochondrial damage, remained unclear. Moderate levels of ROS could promote tumor progression by inducing DNA mutations, genomic instabilities or acting as signaling molecules that accelerate cancer cell proliferation and metastasis [3]. Excessive levels of ROS might enhance cellular oxidative stress, cause DNA/proteins/lipids damage, and lead to apoptotic cell death [4]. Accumulating evidence has identified that mitochondrial dysfunction was always accompanied with interfered oxidative respiratory chain, which might reduce intracellular ATP levels and fail to produce enough energy for tumor growth [9, 10]. Mitochondrial damage induces cytochrome C (Cyto C) leakage from mitochondria into cytosol, while high levels of Cyto C subsequently activate caspase-depended apoptosis pathway [11, 12]. Boosting ROS could be a crucial way for activating mitochondria-depended apoptosis pathway, while precise ROS-generation at GC region is still a big problem
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